The long-term objective of the research program is to delineate the biochemical mechanism of those chemical carcinogen-induced alterations responsible for the biological properties of epithelial cells that are fundamental to the development of malignant growth properties. Chemically induced hepatocarcinogenesis in the adult rat is being used as a model to study the mechanism by which new hepatocyte phenotypes develop altered proliferation control properties during the premalignant phase of the development of liver cancer. Biological analyses of the early events in hepatic neoplasia are currently being focused on one specific hepatocyte population that contains high levels of the enzyme gamma-glutamyl transpeptidase (gamma-GT). This hepatocyte phenotype can be isolated from donor rats, during hepatocarcinogenesis, and quantitatively transferred by surgical techniques to recipient rats where rapid hepatic colonization can be achieved under restrictive conditions. Various physiological parameters of recipient animals are being assessed to determine the mechanism(s) by which carcinogen-altered hepatocytes can be selectively "pushed" into cell proliferation such that differential growth patterns develop in the liver tissue during the premalignant phase of cancer development. The in vitro stage of the transfer procedure is a focal point for efforts to purify specific hepatocyte phenotypes from heterogeneous cell populations dissociated from premalignant liver tissue. The cellular biochemical alterations responsible for the remarkable pan-resistance of these cell populations to the in vitro cytocidal effects of numerous structurally diverse chemical toxins are being sought.